The role of hepatocyte nuclear factor 4-alpha in perfluorooctanoic acid- and perfluorooctanesulfonic acid-induced hepatocellular dysfunction.
The role of hepatocyte nuclear factor 4-alpha in perfluorooctanoic acid- and perfluorooctanesulfonic acid-induced hepatocellular dysfunction.
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DOI：
10.1016/j.taap.2016.05.001
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发表时间：
2016-08-01
影响因子：
3.8
通讯作者：
Apte U
中科院分区：
文献类型：
--
作者：
Beggs KM;McGreal SR;McCarthy A;Gunewardena S;Lampe JN;Lau C;Apte U
全氟辛酸 (PFOA) 和全氟辛烷磺酸 (PFOS) 是多种消费品中存在的化学物质，是持久性有机污染物。这两种化合物都会对啮齿类动物产生肝毒性作用，包括脂肪变性、肝肿大和肝癌。 PFOA 和 PFOS 引起的肝功能障碍的机制尚不完全清楚。我们提供的证据表明，PFOA 和 PFOS 通过靶向肝细胞核因子 4-α (HNF4α) 诱导其肝脏作用。用与职业暴露相关的浓度的 PFOA 和 PFOS 处理的人肝细胞导致 HNF4α 蛋白减少，但不影响 HNF4α mRNA 或导致细胞死亡。 RNA 测序分析与 Ingenuity Pathway 分析相结合，对经 PFOA 或 PFOS 处理的人肝细胞的整体基因表达变化进行分析，表明参与脂质代谢和肿瘤发生的基因表达发生了变化，其中一些基因受 HNF4α 调节。对特定 HNF4α 靶基因表达的进一步研究表明，PFOA 和 PFOS 可以通过下调正靶标（分化基因，如 CYP7A1）和诱导负靶标（促有丝分裂基因，如 CCND1），促进细胞去分化并增加细胞增殖。此外，计算机对接模拟表明，PFOA 和 PFOS 可以以与内源性脂肪酸类似的方式直接与 HNF4α 相互作用。总的来说，这些结果强调了 HNF4α 降解是 PFOA 和 PFOS 介导的人类肝脏脂肪变性和肿瘤发生的新机制。
Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), chemicals present in a multitude of consumer products, are persistent organic pollutants. Both compounds induce hepatotoxic effects in rodents, including steatosis, hepatomegaly and liver cancer. The mechanisms of PFOA- and PFOS-induced hepatic dysfunction are not completely understood. We present evidence that PFOA and PFOS induce their hepatic effects via targeting hepatocyte nuclear factor 4-alpha (HNF4α). Human hepatocytes treated with PFOA and PFOS at a concentration relevant to occupational exposure caused a decrease in HNF4α protein without affecting HNF4α mRNA or causing cell death. RNA sequencing analysis combined with Ingenuity Pathway Analysis of global gene expression changes in human hepatocytes treated with PFOA or PFOS indicated alterations in the expression of genes involved in lipid metabolism and tumorigenesis, several of which are regulated by HNF4α. Further investigation of specific HNF4α target gene expression revealed that PFOA and PFOS could promote cellular dedifferentiation and increase cell proliferation by down regulating positive targets (differentiation genes such as CYP7A1) and inducing negative targets of HNF4α (pro-mitogenic genes such as CCND1). Furthermore, in silico docking simulations indicated that PFOA and PFOS could directly interact with HNF4α in a similar manner to endogenous fatty acids. Collectively, these results highlight HNF4α degradation as novel mechanism of PFOA and PFOS-mediated steatosis and tumorigenesis in human livers.